Enhancing muscle quality as a clinical endpoint

Abstract

Provided are methods for assessing muscle improvement in a subject, comprising measuring one or more muscle quality parameters in a subject, administering to the subject a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, and measuring one or more muscle quality parameters in the subject after being administered the 15-PGDH inhibitor.

Description

Attorney Docket No.55773-739.601 ENHANCING MUSCLE QUALITY AS A CLINICAL ENDPOINT CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 657,064, filed on June 6, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Muscle mass and function may decrease with aging, after injury, or as a consequence of disease. The relevant parameters for assessing muscle function and quality are unclear, and therapeutics which increase muscle mass have not demonstrated clear improvements in muscle quality. There is an unmet need for methods that accurately assess muscle improvement and therapeutics which improve muscle quality. INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. SUMMARY

[0004] There is an unmet need for methods for assessing muscle improvement in a subject. This disclosure meets this unmet need by identifying muscle parameters that can be used in methods for assessing muscle improvement after administering a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor.

[0005] In one aspect, provided herein is a method for assessing muscle improvement in a subject, the method comprising: measuring one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time -1-Attorney Docket No.55773-739.601 of the muscle contraction, sustain time of the muscle contraction, or combinations thereof; administering to the subject a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and measuring one or more muscle quality parameters in the subject after being administered the 15-PGDH inhibitor.

[0006] In some embodiments, the one or more muscle quality parameters in the subject is grip strength.

[0007] In some embodiments, the one or more muscle quality parameters in the subject is time to complete a Timed-Up-and-Go assessment.

[0008] In some embodiments, prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased muscle contraction time in response to a stimulus relative to a predetermined threshold.

[0009] In some embodiments, after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having decreased muscle contraction time in response to a stimulus relative to step a).

[0010] In some embodiments, prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having reduced grip strength relative to a predetermined threshold.

[0011] In some embodiments, after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased grip strength relative to step a).

[0012] In some embodiments, prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased time to complete a Timed-Up-and-Go assessment relative to a predetermined threshold.

[0013] In some embodiments, after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having decreased time to complete a Timed-Up-and-Go assessment relative to step a).

[0014] In some embodiments, measuring one or more muscle quality parameters in the subject in step a) identifies the subject as a candidate for treatment with the 15-PGDH inhibitor.

[0015] In some embodiments, the subject has a disease or condition associated with reduced muscle quality.

[0016] In some embodiments, the disease or condition associated with reduced muscle quality is associated with aging.

[0017] In some embodiments, the disease or condition associated with aging is sarcopenia. -2-Attorney Docket No.55773-739.601

[0018] In some embodiments, the disease or condition associated with reduced muscle quality is spinal muscular atrophy.

[0019] In some embodiments, the disease or condition associated with reduced muscle quality is due to muscle injury.

[0020] In some embodiments, the administering is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof.

[0021] In some embodiments, the administering is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration.

[0022] In some embodiments, the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier.

[0023] In some embodiments, the subject is administered a gastric inhibitory polypeptide (GIP) receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, an incretin mimetic, or a GLP-1 analog.

[0024] In some embodiments, the subject is a human.

[0025] In some embodiments, the muscle comprises fast-twitch muscle fibers.

[0026] In some embodiments, the muscle is extensor digitorum longus.

[0027] In some embodiments, the one or more muscle quality parameters is independent of muscle weight.

[0028] In some embodiments, the subject is at least 60 years old.

[0029] In some embodiments, the 15-PGDH inhibitor is selected from the group consisting of: a small molecule, an antibody or fragment thereof, a peptide inhibitor, an aptamer, an oligonucleotide inhibitor, and any combination thereof.

[0030] In another aspect, provided herein is a method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject exhibits improvement in muscle quality as measured in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle -3-Attorney Docket No.55773-739.601 contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof.

[0031] In another aspect, provided herein is a method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject is identified as meeting a clinical endpoint, wherein the clinical endpoint is measured by an improvement in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof. In some embodiments, the improvement is an improvement of at least 5% as compared to a baseline measurement in one or more of the muscle quality parameters.

[0032] In another aspect, provided herein is a method for improving muscle quality in a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, wherein the subject exhibits improvement in muscle quality as measured by an increase in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof, wherein the improvement is an improvement of at least 5% as compared to a baseline measurement in one or more of the muscle quality parameters. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: -4-Attorney Docket No.55773-739.601

[0034] FIGs.1A-1E show the effects of administration of a 15-PGDH inhibitor in aged mouse muscle. FIG.1A shows the effect of administration of the 15-PGDH inhibitor on absolute force in extensor digitorum longus (EDL) muscle. FIG.1B shows the effect of administration of the 15-PGDH inhibitor on specific force in EDL muscle. FIG.1C shows the effect of administration of the 15-PGDH inhibitor on contraction rate in EDL muscle. FIG.1D shows EDL muscle weight in adult and aged mice administered either vehicle or the 15-PGDH inhibitor. FIG.1E shows a comparison between the effects of therapeutic molecules in multiple mouse models and targeted muscles on parameters. DETAILED DESCRIPTION

[0035] Muscle mass, muscle function, and muscle quality may decrease with aging, after injury, or as a consequence of disease. Therapeutics directed to treating reduced muscle quality resulting from aging, injury, or disease have used increases in muscle mass as an indicator of muscle improvement. However, in some instances, pharmacological treatments which increase muscle mass do not result in an associated increase in muscle quality. For example, myostatin inhibitors have been shown to increase muscle size without improving muscle quality. In order to identify therapeutics useful for improving muscle quality, there is a need for identifying relevant parameters that indicate improvements in muscle function and quality.

[0036] Provided herein are methods for assessing muscle improvement in a subject and methods for treating a subject with a muscle disorder. The methods provided herein generally involve administering a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to a subject. The methods provided herein also generally involve measuring or assessing muscle quality parameters or identifying a clinical endpoint in the subject.

[0037] In one aspect, provided herein is a method for assessing muscle improvement in a subject comprising measuring one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof; administering to the subject a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and measuring -5-Attorney Docket No.55773-739.601 one or more muscle quality parameters in the subject after being administered the 15-PGDH inhibitor.

[0038] In some cases, provided herein is method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject exhibits improvement in muscle quality as measured by an increase in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof.

[0039] In some cases, provided herein is a method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject is identified as meeting a clinical endpoint, wherein the clinical endpoint is measured by an increase in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof, and wherein the improvement is identified as an increase from a baseline measurement of at least 5% in one or more of the muscle quality parameters.

[0040] In some cases, provided herein is a method for improving muscle quality in a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, wherein the subject exhibits improvement in muscle quality as measured by an increase in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, -6-Attorney Docket No.55773-739.601 or combinations thereof, wherein the improvement is identified as an increase from a baseline measurement of at least 5% in one or more of the muscle quality parameters.

[0041] In some embodiments, prior to administering to the subject the 15-PGDH inhibitor, the subject is identified as having increased muscle contraction time in response to a stimulus relative to a predetermined threshold. In some embodiments, after administering to the subject the 15-PGDH inhibitor, the subject is identified as having decreased muscle contraction time in response to a stimulus. In some embodiments, absolute force of a muscle contraction is an indicator of muscle quality. For example, FIG.1A shows that absolute force in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. In some embodiments, specific force of a muscle contraction is an indicator of muscle quality. For example, FIG.1B shows that the specific force in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. In some embodiments, contraction rate is an indicator of muscle quality. For example, FIG.1C shows that contraction rate in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. In some embodiments, contraction time of a muscle contraction is an indicator of muscle quality. In some embodiments, improving muscle quality is a clinical endpoint. In some embodiments, a decrease in muscle contraction time is an improvement. In some embodiments, a decrease in muscle contraction time compared to a baseline measurement indicates an improvement. In some embodiments, an improvement in muscle contraction time assessment is a percent decrease in time to complete a muscle contraction compared to a baseline measurement.

[0042] In some embodiments, the muscle quality parameter is grip strength. In some embodiments, grip strength in a subject is between 0 kilograms and 80 kilograms. In some embodiments, grip strength is measured with a dynamometer. In some embodiments, grip strength is measured in forearm muscles. In some embodiments, grip strength is measured in flexor digitorum superficialis, pronator teres, flexor carpi radialis, flexor carpi ulnaris, or palmaris longus. In some embodiments, grip strength in a subject increases after administration of a 15-PGDH inhibitor. In some embodiments, prior to administering to the subject the 15-PGDH inhibitor, the subject is identified as having reduced grip strength relative to a predetermined threshold. In some embodiments, after administering to the subject the 15-PGDH inhibitor, the subject is identified as having increased grip strength. In some embodiments, an increase in grip strength in the subject compared to a baseline -7-Attorney Docket No.55773-739.601 measurement indicates an improvement. In some embodiments, an improvement in grip strength is a percent increase in grip strength compared to a baseline measurement.

[0043] In some embodiments, the muscle quality parameter is time to complete a Timed-Up- and-Go (TUG) assessment. In some embodiments, TUG assessments comprise multiple phases, including sit-to-stand, walking-out, turning, walking-in, turning around, and stand-to- sit. In embodiments, the subject has to walk less than 3 meters during the TUG assessment. In some embodiments, the subject has to walk 3 meters or more during the TUG assessment. In some embodiments, the TUG assessment takes 5 to 20 seconds to complete. In some embodiments, the TUG assessment takes 10 to 40 seconds to complete. In some embodiments, the TUG assessment takes 1 to 10 seconds to complete. In some embodiments, the TUG assessment takes 1 to 120 seconds to complete. In some embodiments, the TUG assessment takes 10 to 30 seconds to complete. In some embodiments, the TUG assessment takes 10 to 100 seconds to complete. In some embodiments, the TUG assessment takes 5 to 30 seconds to complete. In some embodiments, the TUG assessment takes 1 to 180 seconds to complete. In some embodiments, the TUG assessment takes 30 to 60 seconds to complete.

[0044] In some embodiments, time to complete the TUG assessment for a subject decreases after administration of a 15-PGDH inhibitor. In some embodiments, the muscle quality parameter is independent of muscle weight. In some embodiments, muscle weight does not vary as a consequence of aging or pharmacological treatment. For example, FIG.1D shows that EDL muscle weight did not vary as a consequence of either mouse age or 15-PGDH inhibitor treatment. In some embodiments, prior to administering to the subject the 15-PGDH inhibitor, the subject is identified as having increased time to complete a TUG assessment relative to a predetermined threshold. In some embodiments, after administering to the subject the 15-PGDH inhibitor, the subject is identified as having a decrease in time to complete a TUG assessment. In some embodiments, a decrease in time to complete a TUG assessment identifies an improvement. In some embodiments, a decrease in time to complete a TUG assessment compared to a baseline measurement indicates an improvement. In some embodiments, an improvement in time to complete a TUG assessment is a percent decrease in time to complete a TUG assessment compared to a baseline measurement.

[0045] In some embodiments, an improvement in muscle quality is an improvement in a muscle quality parameter. In some embodiments, the improvement is a percent improvement as compared to a baseline measurement for the muscle quality parameter, for example, an increase in grip strength of at least 5% as compared to a baseline measurement before treatment, or a decrease in TUG assessment time of at least 5% as compared to a baseline -8-Attorney Docket No.55773-739.601 measurement before treatment. In some embodiments, the improvement is an improvement of at least 5% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 10% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 15% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 20% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 25% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 30% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 35% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 40% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 45% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 50% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 60% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 70% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 80% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 90% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 95% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 99% as compared to a baseline measurement in one or more of the muscle quality parameters. In some embodiments, the improvement is an improvement of at least 100% or more as compared to a baseline measurement in one or more of the muscle quality parameters.

[0046] The 15-PGDH inhibitor may be administered to the subject in an amount that is effective to improve muscle quality in the subject. In some embodiments, measuring one or -9-Attorney Docket No.55773-739.601 more muscle quality parameters in the subject identifies the subject as a candidate for treatment with the 15-PGDH inhibitor. In some embodiments, the effective dose of the 15- PGDH inhibitor comprises about 1 mg / kg (or about 1MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises at least about 1 mg / kg (or at least about 1MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises less than about 1 mg / kg (or 1MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg.

[0047] In some embodiments, the subject has a condition. In some embodiments, the condition is a muscle condition. In some embodiments, the condition is spinal muscular atrophy (SMA). In some embodiments, the condition is a disease. In some embodiments, the disease is a muscle disease. In some embodiments, the muscle condition is muscle atrophy, muscle damage, muscle disorder, or muscle injury. In some embodiments, the muscle disease is associated with muscle atrophy, muscle damage, or muscle injury. In some embodiments, the subject has a disease or condition associated with reduced muscle quality. In some embodiments, the disease or condition associated with reduced muscle quality is associated with aging. In some embodiments, the disease or condition associated with aging is sarcopenia. In some embodiments, the disease or condition associated with reduced muscle quality is spinal muscular atrophy. In some embodiments, the disease or condition associated with reduced muscle quality is due to muscle injury.

[0048] In some embodiments, the condition associated with muscle damage, injury, or atrophy is selected from the group consisting of acute muscle injury or trauma, soft tissue hand injury, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), inherited myopathies, myotonic muscular dystrophy (MDD), mitochondrial myopathies, myotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, -10-Attorney Docket No.55773-739.601 cardiac cachexia, stress induced urinary incontinence, and sarcopenia. In some embodiments, improving muscle quality is a clinical endpoint.

[0049] In some embodiments, the muscle to be measured can be any muscle of the body, including but not limited to, musculi pectoralis complex, latissimus dorsi, teres major and subscapularis, brachioradialis, biceps, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum profundus, flexor pollicis brevis, opponens pollicis, adductor pollicis, flexor pollicis brevis, iliopsoas, psoas, rectus abdominis, rectus femoris, gluteus maximus, gluteus medius, medial hamstrings, gastrocnemius, lateral hamstring, quadriceps mechanism, adductor longus, adductor brevis, adductor magnus, gastrocnemius medial, gastrocnemius lateral, soleus, tibialis posterior, tibialis anterior, flexor digitorum longus, flexor digitorum brevis, flexor hallucis longus, extensor hallucis longus, extensor digitorum longus, hand muscles, arm muscles, foot muscles, leg muscles, chest muscles, stomach muscles, back muscles, buttock muscles, shoulder muscles, head and neck muscles, facial muscles, oculopharyngeal muscles, and the like. In some embodiments, the muscle is extensor digitorum longus (EDL).

[0050] In some embodiments, the muscle can be composed of different types of muscle fibers. In some embodiments, the muscle fibers are type I, type IC, type IIC, type IIA, type IIAB, or type IIB muscle fibers. In some embodiments, these muscle fibers are slow-twitch muscle fibers or fast-twitch muscle fibers. In some embodiments, the muscle comprises fast- twitch muscle fibers. In some embodiments, the fast-twitch muscle fibers can comprise ATPase type II or MHC type II fibers. In some embodiments, the slow-twitch muscle fibers can comprise ATPase type I or MHC type I fibers. In some embodiments, the subject is a human. In some embodiments, the muscles are in an aged subject. In some embodiments, the aged subject is at least 60 years old. In some embodiments, the aged subject is over 70 years old.

[0051] In some embodiments, the muscle condition comprises musculoskeletal injuries (e.g., fractures, strains, sprains, acute injuries, overuse injuries, and the like), post-trauma damages to limbs or face, athletic injuries, post-fractures in the aged, soft tissue hand injuries, muscle atrophy (e.g., loss of muscle mass), Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, myotonic dystrophy, other muscular dystrophies, muscle wasting disease, such as cachexia -11-Attorney Docket No.55773-739.601 due to cancer, end stage renal disease (ESRD), acquired immune deficiency syndrome (AIDS), or chronic obstructive pulmonary disease (COPD), post-surgical muscle weakness, post-traumatic muscle weakness, sarcopenia, inactivity (e.g., muscle disuse or immobility), urethral sphincter deficiency, urethral sphincter deficiency, neuromuscular disease, and the like. In some cases, the subject has a disease or condition associated with elevated levels of p75 extracellular domain (p75 ECD). In some cases, the disease or condition associated with elevated levels of p75ECD is a neurodegenerative disorder. In some cases, the neurodegenerative disorder is amyotrophic lateral sclerosis or Alzheimer’s disease. In some cases, the subject has a disease or condition associated with elevated levels of Urinary Prostaglandin E-metabolite (PGE-M). In some embodiments, biomarkers predict the effectiveness of 15-PGDH inhibitor treatment. In some embodiments, levels of p75ECD or PGE-M are biomarkers that predict the effectiveness of 15-PGDH inhibitor treatment. In some embodiments, biomarkers are used to guide 15-PGDH dose selection.

[0052] In some embodiments, the muscle condition comprises a neuromuscular disease. In some embodiments, the neuromuscular diseases include, but are not limited to, acid maltase deficiency, amyotrophic lateral sclerosis, Andersen-Tawil syndrome, Becker muscular dystrophy, Becker myotonia congenita, Bethlem myopathy, bulbospinal muscular atrophy, carnitine deficiency, carnitine palmityl transferase deficiency, central core disease, centronuclear myopathy, Charcot-Marie-Tooth disease, congenital muscular dystrophy, congenital myasthenic syndromes, congenital myotonic dystrophy, Cori disease, Debrancher enzyme deficiency, Dejerine-Sottas disease, dermatomyositis, distal muscular dystrophy, Duchenne muscular dystrophy, dystrophia myotonica, Emery-Dreifuss muscular dystrophy, endocrine myopathies, Eulenberg disease, facioscapulohumeral muscular dystrophy, tibial distal myopathy, Friedreich's ataxia, Fukuyuma congenital muscular dystrophy, glycogenosis type 10, glycogenosis type 11, glycogenosis type 2, glycogenosis type 3, glycogenosis type 5, glycogenosis type 7, glycogenosis type 9, Gowers-Laing distal myopathy, hereditary inclusion-body myositis, hyperthyroid myopathy, hypothyroid myopathy, inclusion-body myositis, inherited myopathies, integrin-deficient congenital muscular dystrophy, spinal- bulbar muscular atrophy, spinal muscular atrophy, lactate dehydrogenase deficiency, Lambert-Eaton myasthenic syndrome, McArdel disease, merosin-deficient congenital muscular dystrophy, metabolic diseases of muscle, mitochondrial myopathy, Miyoshi distal myopathy, motor neuron disease, muscle-eye-brain disease, myasthenia gravis, myoadenylate deaminase deficiency, myofibrillar myopathy, myophosphorylase deficiency, myotonia congenital, myotonic muscular dystrophy, myotubular myopathy, nemaline myopathy, -12-Attorney Docket No.55773-739.601 Nonaka distal myopathy, oculopharyngeal muscular dystrophy, paramyotonia congenital, Pearson syndrome, periodic paralysis, phosphofructokinase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, phosphorylase deficiency, polymyositis, Pompe disease, progressive external ophthalmoplegia, spinal muscular atrophy, Ullrich congenital muscular dystrophy, Welander distal myopathy, ZASP-related myopathy, and the like.

[0053] In some embodiments, muscle atrophy (e.g., muscle wasting) can be caused by or associated with, for example, normal aging (e.g., sarcopenia), genetic abnormalities (e.g., mutations or single nucleotide polymorphisms), poor nourishment, poor circulation, loss of hormonal support, disuse of the muscle due to lack of exercise (e.g., bedrest, immobilization of a limb in a cast, etc.), aging, damage to the nerve innervating the muscle, poliomyelitis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), heart failure, liver disease, diabetes, obesity, metabolic syndrome, demyelinating diseases (e.g., multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, and Guillian-Barre syndrome), denervation, fatigue, exercise-induced muscle fatigue, frailty, neuromuscular disease, weakness, chronic pain, and the like.

[0054] In some embodiments, the condition is hair loss. In some embodiments, the condition is skin inflammation and / or damage. In some embodiments, the condition is vascular insufficiency. In some embodiments, the condition is congestive heart failure or cardiomyopathy. In some embodiments, the condition is a gastrointestinal disease. In some embodiments, the condition is renal dysfunction. In some embodiments, the condition is a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. In some embodiments, the condition is a fibrotic or adhesion disease, disorder, or condition. In some embodiments, the condition is scar formation. In some embodiments, the condition is fibrosis. In some embodiments, the condition is idiopathic pulmonary fibrosis. In some embodiments, the condition is kidney fibrosis. In some embodiments, the condition is acute kidney injury. In some embodiments, the condition is sarcopenia. In some embodiments, the condition is a neuromuscular disease.

[0055] In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by various methods. For example, oral administration, intramuscular administration, intradermal administration, subcutaneous administration, intrathecal administration, intravenous administration, intraperitoneal administration, topical (transdermal), instillation, and implantation (for example, of a slow-release device such as -13-Attorney Docket No.55773-739.601 polymeric implant or miniosmotic pump) can all be appropriate routes of administration. In some embodiments, the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by intramuscular administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by intraperitoneal injection.

[0056] In some embodiments, the subject is administered a gastric inhibitory polypeptide (GIP) receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, an incretin mimetic, or a GLP-1 analog. In some embodiments, the effective dose of the gastric inhibitory polypeptide (GIP) receptor agonist, glucagon-like peptide-1 (GLP-1) receptor agonist, incretin mimetic, or GLP-1 analog comprises about 1 nmol / kg, about 3 nmol / kg, about 10 nmol / kg, about 20 nmol / kg, about 30 nmol / kg, about 40 nmol / kg, about 50 nmol / kg, about 60 nmol / kg, about 70 nmol / kg, about 80 nmol / kg, about 90 nmol / kg, or about 100 nmol / kg.

[0057] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0058] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, wherein: X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, – SCH2–, –S(O)CH2–, –SO2CH2–; each Y is independently selected from N and CR11; each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or -14-Attorney Docket No.55773-739.601 R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl;each R11 is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -15-Attorney Docket No.55773-739.601 provided that said compound of Formula I is not,.

[0059] In some embodiments, X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, – C(O)NMe–, –NMeC(O)–, –SCH2–, –S(O)CH2–, and –SO2CH2–. In some embodiments, X is –OCH2–. In some embodiments, X is –C(O)NH–. In some embodiments, X is –NHC(O)–. In some embodiments, X is –C(O)NMe–. In some embodiments, X is –NMeC(O)–. In some embodiments, X is –SCH2–. In some embodiments, X is –S(O)CH2–. In some embodiments, X is –SO2CH2–.

[0060] In some embodiments, each Y is independently selected from N and CR11. In some embodiments, each Y is N. In some embodiments, each Y is CR11. In some embodiments, one Y is N and the other Y is CR11.

[0061] In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R1is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,–NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0062] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio. -16-Attorney Docket No.55773-739.601

[0063] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0064] In some embodiments, each R5is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments,each R5 is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0065] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, and C1-6alkyl.

[0066] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H, and C1-6alkyl.

[0067] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- -17-Attorney Docket No.55773-739.601 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0068] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0069] In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0070] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0071] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0072] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0073] In some embodiments, the compound is a compound of Formula Ia:

[0074] -18-Attorney Docket No.55773-739.601 Formula Ia

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compound is a compound of Formula Ib:Formula Ib

[0077] or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the 15-PGDH inhibitor is a compound of Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently selected from N and CR5; S, V, and Z are independently selected from N and C; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently -19-Attorney Docket No.55773-739.601 selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that said compound of Formula II is not,-20-Attorney Docket No.55773-739.601-21-Attorney Docket No.55773-739.601. -22-Attorney Docket No.55773-739.601

[0079] In some embodiments, T, U, W, X, and Y are independently selected from N and CR5. In some embodiments, at least one of T, U, W, X, and Y is N and the rest are CR5. In some embodiments, at least two of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least three of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least four of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, T, U, W, X, and Y are CR5. In some embodiments, T, U, W, X, and Y are N.

[0080] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the rest are C. In some embodiments, at least two of S, V, and Z are N and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0081] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7. -23-Attorney Docket No.55773-739.601

[0082] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0083] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is halo. In some embodiments, each R4is fluoro.

[0084] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-memberedheterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, twoR4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, – NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, and –C(O)NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo. In some embodiments, two -24-Attorney Docket No.55773-739.601 R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are fluoro.

[0085] In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R5is independently selected from H and halo.

[0086] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0087] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0088] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0089] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected -25-Attorney Docket No.55773-739.601 from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0090] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0091] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0092] In some embodiments, the compound is a compound of Formula IIa: Formula IIa or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0093] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0094] In some embodiments, the compound is a compound of Formula IIb:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0095] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0096] In some embodiments, the compound is a compound of Formula IIc: -26-Attorney Docket No.55773-739.601Formula IIc or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0097] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0098] In some embodiments, compound is a compound of Formula IId:Formula IId or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0099] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0100] In some embodiments, the compound is a compound of Formula IIe:Formula IIe or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0101] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. -27-Attorney Docket No.55773-739.601

[0102] In some embodiments, the compound is a compound of Formula IIf:Formula IIf or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0103] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0104] In some embodiments, the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0105] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0106] In some embodiments, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0107] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0108] In some embodiments, the compound is a compound of Formula IIi: -28-Attorney Docket No.55773-739.601or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0109] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0110] In some embodiments, the compound is a compound of Formula IIj:Formula IIj or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0111] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0112] In some embodiments, the compound is a compound of Formula IIn:Formula IIn or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0113] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0114] In some embodiments, the compound is a compound of Formula IIp: -29-Attorney Docket No.55773-739.601Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0115] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0116] In some embodiments, the 15-PGDH inhibitor is a compound of Formula III:Formula III or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3- 10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- -30-Attorney Docket No.55773-739.601 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3- 10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; -31-Attorney Docket No.55773-739.601 each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0117] In some embodiments, each X is independently selected from N and CR7. In some embodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0118] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0119] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl,C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl.In some embodiments, R1is selected from C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, -32-Attorney Docket No.55773-739.601 –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0120] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0121] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 -33-Attorney Docket No.55773-739.601 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0122] In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0123] In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10. -34-Attorney Docket No.55773-739.601

[0124] In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0125] In some embodiments, each R7is independently selected from H, halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11,–NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0126] In some embodiments, each R8is independently selected from H, halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R8is independently selected from H, halo, -35-Attorney Docket No.55773-739.601 –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R8is independently selected from H, halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0127] In some embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, two R8’s can be taken together to form a C3- 10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. Insome embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0128] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl.

[0129] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1- 6alkyl. -36-Attorney Docket No.55773-739.601

[0130] In some embodiments, each R12is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0131] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0132] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0133] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0134] In some embodiments, the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3. -37-Attorney Docket No.55773-739.601

[0136] In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

[0137] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0138] In some embodiments, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is a compound of Formula IIId:Formula IIId or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – -38-Attorney Docket No.55773-739.601 NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0140] In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

[0141] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0142] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIk:Formula IIk or a pharmaceutically acceptable salt thereof, wherein: T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, – -39-Attorney Docket No.55773-739.601 NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo; R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, – SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, – SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R11 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; andp is 0, 1, or 2.

[0143] In some embodiments, T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N. In some embodiments, one of T, U, and Y is N and the rest are CR6. In some embodiments, two of T, U, and Y are N and the rest are CR6. In some embodiments, one of T, U, and Y is CR6and the rest are N. In some embodiments, two of T, U, and Y are CR6and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR6.

[0144] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 -40-Attorney Docket No.55773-739.601 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, – C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, – OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, – NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, – C(O)R9, –C(O)OR9, and –C(O)NR7R8.

[0145] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0146] In some embodiments, each R4is independently selected from H and halo. In some embodiments, each R4is independently selected from H and fluoro. In some embodiments, each R4is H. In some embodiments, each R4is fluoro. In some embodiments, one R4is H and one R4is fluoro.

[0147] In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In someembodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, – SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, and – C(O)NR7R8.

[0148] In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, – C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, – C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6is -41-Attorney Docket No.55773-739.601 selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, and – C(O)NR7R8.

[0149] In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H and C1-6alkyl.

[0150] In some embodiments, each R9is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from H and C1-6alkyl.

[0151] In some embodiments, each R10is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from C1-6alkyl.

[0152] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-6cycloalkyl. In some embodiments, each R11is independently selectedfrom H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R11 is independentlyselected from H and C1-6alkyl.

[0153] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0154] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, – -42-Attorney Docket No.55773-739.601 NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0155] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 -43-Attorney Docket No.55773-739.601 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0156] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0157] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0158] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some -44-Attorney Docket No.55773-739.601 embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0159] In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7.

[0160] In some embodiments, R6 and R7 are independently selected at each occurrence fromH, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0161] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0162] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0163] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected -45-Attorney Docket No.55773-739.601 from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0164] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0165] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0166] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0167] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, – NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – -46-Attorney Docket No.55773-739.601 SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0168] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, and –C(O)NR6R7. -47-Attorney Docket No.55773-739.601

[0169] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0170] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0171] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to10-membered heteroaryl. In some embodiments, two R4’s are taken together with the carbonatoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0172] In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, -48-Attorney Docket No.55773-739.601 –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7.

[0173] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0174] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0175] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. Insome embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0176] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0177] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0178] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. -49-Attorney Docket No.55773-739.601

[0179] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0180] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3- 6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – -50-Attorney Docket No.55773-739.601 NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0181] In some embodiments, each X is independently selected from N and CR7. In someembodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0182] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0183] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – -51-Attorney Docket No.55773-739.601 C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0184] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0185] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 -52-Attorney Docket No.55773-739.601 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0186] In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0187] In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10. -53-Attorney Docket No.55773-739.601

[0188] In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0189] In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0190] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl. -54-Attorney Docket No.55773-739.601

[0191] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1- 6alkyl.

[0192] In some embodiments, each R12is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0193] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0194] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0195] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:-55-Attorney Docket No.55773-739.601

[0196] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of: ;; -56-Attorney Docket No.55773-739.601-57-Attorney Docket No.55773-739.601-58-Attorney Docket No.55773-739.601;-59-Attorney Docket No.55773-739.601-60-Attorney Docket No.55773-739.601-61-Attorney Docket No.55773-739.601 ;-62-Attorney Docket No.55773-739.601-63-Attorney Docket No.55773-739.601 ;-64-Attorney Docket No.55773-739.601-65-Attorney Docket No.55773-739.601-66-Attorney Docket No.55773-739.601 ;

[0198] In some cases, the solubility and hPGDH IC50 of the inhibitors are characterized as shown in Tables 1 and 2. Table 1: Characteristics of PGDH Inhibitors with a 6-5 ring core. -67-Attorney Docket No.55773-739.601-68-Attorney Docket No.55773-739.601-69-Attorney Docket No.55773-739.601-70-Attorney Docket No.55773-739.601-71-Attorney Docket No.55773-739.601-72-Attorney Docket No.55773-739.601-73-Attorney Docket No.55773-739.601Table 2: Characteristics of PGDH Inhibitors with a phenyl core.-74-Attorney Docket No.55773-739.601

[0199] Provided in Table 3 are analytical data for some of the inhibitors described herein. Table 3: Analytical data for select inhibitors -75-Attorney Docket No.55773-739.601-76-Attorney Docket No.55773-739.601-77-Attorney Docket No.55773-739.601-78-Attorney Docket No.55773-739.601-79-Attorney Docket No.55773-739.601-80-Attorney Docket No.55773-739.601-81-Attorney Docket No.55773-739.601-82-Attorney Docket No.55773-739.601-83-Attorney Docket No.55773-739.601-84-Attorney Docket No.55773-739.601-85-Attorney Docket No.55773-739.601-86-Attorney Docket No.55773-739.601-87-Attorney Docket No.55773-739.601-88-Attorney Docket No.55773-739.601-89-Attorney Docket No.55773-739.601-90-Attorney Docket No.55773-739.601-91-Attorney Docket No.55773-739.601-92-Attorney Docket No.55773-739.601-93-Attorney Docket No.55773-739.601-94-Attorney Docket No.55773-739.601-95-Attorney Docket No.55773-739.601-96-Attorney Docket No.55773-739.601-97-Attorney Docket No.55773-739.601-98-Attorney Docket No.55773-739.601-99-Attorney Docket No.55773-739.601-100-Attorney Docket No.55773-739.601-101-Attorney Docket No.55773-739.601-102-Attorney Docket No.55773-739.601-103-Attorney Docket No.55773-739.601-104-Attorney Docket No.55773-739.601-105-Attorney Docket No.55773-739.601-106-Attorney Docket No.55773-739.601-107-Attorney Docket No.55773-739.601-108-Attorney Docket No.55773-739.601-109-Attorney Docket No.55773-739.601-110-Attorney Docket No.55773-739.601-111-Attorney Docket No.55773-739.601-112-Attorney Docket No.55773-739.601-113-Attorney Docket No.55773-739.601-114-Attorney Docket No.55773-739.601-115-Attorney Docket No.55773-739.601-116-Attorney Docket No.55773-739.601-117-Attorney Docket No.55773-739.601-118-Attorney Docket No.55773-739.601-119-Attorney Docket No.55773-739.601-120-Attorney Docket No.55773-739.601-121-Attorney Docket No.55773-739.601-122-Attorney Docket No.55773-739.601-123-Attorney Docket No.55773-739.601-124-Attorney Docket No.55773-739.601-125-Attorney Docket No.55773-739.601-126-Attorney Docket No.55773-739.601-127-Attorney Docket No.55773-739.601-128-Attorney Docket No.55773-739.601-129-Attorney Docket No.55773-739.601-130-Attorney Docket No.55773-739.601

[0200] In some embodiments, the 15-PGDH inhibitor is a compound of having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV, wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; -131-Attorney Docket No.55773-739.601 each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3- C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substitutedor unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, -132-Attorney Docket No.55773-739.601 substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;each Ra is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0201] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; -133-Attorney Docket No.55773-739.601 Z is CR1or N; Y is CR2of N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R2is H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently H, halogen, CN,-NO2, –NR8R9, -OH, –OR10, -SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl, or 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3- C6 cycloalkyl ring; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a C3- C6 cycloalkyl ring; each R8and R9is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, and C4-C10heterocycloalkyl; each R10is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; -134-Attorney Docket No.55773-739.601 each R12is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; and p is 1, 2, 3, or 4.

[0202] In some embodiments, ring Q is 5- to 10-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0203] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is a phenyl, pyrimidine, or pyridine. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine. In some embodiments, ring Q is pyridine.

[0204] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0205] In some embodiments,, wherein, X1, X2, X3and X4are each independently N or CR3; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R13; each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, -135-Attorney Docket No.55773-739.601 substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; andeach Ra is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0206] In some embodiments, X1, X2, X3and X4are each CR3.

[0207] In some embodiments, X1is N; and X2, X3, and X4are each CR3.

[0208] In some embodiments, X1and X2are each N; and X3and X4are each CR3.

[0209] In some embodiments, X1and X3are each N; and X2and X4are each CR3.

[0210] In some embodiments, X1and X4are each N; and X2and X3are each CR3.

[0211] In some embodiments, X1, X2, and X3are each N; and X4is CR3.

[0212] In some embodiments, X1, X2, and X4are each N; and X3is CR3.

[0213] In some embodiments, each R3is independently selected from H, halogen, -CN, - NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, – SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 -136-Attorney Docket No.55773-739.601 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, –C(O)R10, –C(O)OR10, – C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0214] In some embodiments, each R3is independently selected from H or halogen. In some embodiments, each R3is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently a substituted or unsubstituted 5-membered heteroaryl.

[0215] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3- C8 cycloalkyl; R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, – -137-Attorney Docket No.55773-739.601 NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 -138-Attorney Docket No.55773-739.601 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3

[0216] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H; each R2is independently H or C1-C6 alkyl; R3a, R3b, and R3care each independently selected from H, halogen, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and -139-Attorney Docket No.55773-739.601 substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3;or R5a and one R6 combine together with the atom(s) to which they are attached to form asubstituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted -140-Attorney Docket No.55773-739.601 or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0217] In some embodiments, XAis NR5R5. In some embodiments, XAis OR5.

[0218] In some embodiments, Y is N. In some embodiments, Y is CR2.

[0219] In some embodiments, the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

[0220] In some embodiments, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

[0221] In some embodiments, Z is N. In some embodiments, Z is CR1. In some embodiments, Z is CH. -141-Attorney Docket No.55773-739.601

[0222] In some embodiments, the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:Formula VIIa.

[0223] In some embodiments, the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula (IVb).

[0224] In some embodiments, the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:Formula VIIc.

[0225] In some embodiments, the compound of Formula V has the structure of Formula VIId, or a pharmaceutically acceptable salt thereof:-142-Attorney Docket No.55773-739.601 Formula VIId.

[0226] In some embodiments, R1is H, halogen, –OR10, –C(O)R10, –C(O)OR10, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R1is H.

[0227] In some embodiments, each R2is independently H, halogen, –OR10, –C(O)R10, – C(O)OR10, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, each R2is independently H or C1-C6 alkyl.

[0228] In some embodiments, each R2is H.

[0229] In some embodiments, X1is CR3a. In some embodiments, X1is N.

[0230] In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -S8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independentlyselected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)R10, –C(O)NR8R9, and substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –OR10, -S8,–C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,– NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, –C(O)R10, –C(O)NR8R9, C3-C6heterocycloalkyl, and 5- membered heteroaryl.

[0231] In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)OH, –C(O)NH2, –C(O)NH(CH3), –C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or C1-C6 alkyl substituted with -C(O)OH. -143-Attorney Docket No.55773-739.601

[0232] In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, – NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from substituted or unsubstituted C1-C6 alkyl, – C(O)R10, –C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis a substituted or unsubstituted 5- membered heteroaryl.

[0233] In some embodiments, R3ais halogen and R3bis H. In some embodiments, R3ais -Cl or -F; and R3bis H. In some embodiments, R3bis halogen and R3ais H. In some embodiments, R3bis -Cl or -F; and R3ais H.

[0234] In some embodiments, R3aand R3bare each H.

[0235] In some embodiments, R3aand R3care independently H or halogen; and R3bis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, – SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, – NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or -144-Attorney Docket No.55773-739.601 unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from –C(O)R10, –C(O)OR10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3care each H or halogen; and R3bis selected from substituted or unsubstituted C1-C6 alkyl, –C(O)R10, – C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl.

[0236] In some embodiments, R3aand R3care each H or halogen; and R3bis selected from – C(O)R10, –C(O)OR10and substituted or unsubstituted 5-membered heteroaryl.

[0237] In some embodiments, R3ais halogen and R3cis H. In some embodiments, R3ais H and R3bis halogen. In some embodiments, R3ais -Cl or -F; and R3cis H. In some embodiments, R3cis -Cl or -F; and R3ais H.

[0238] In some embodiments, R3aand R3care each H.

[0239] In some embodiments, each R3, R3a, R3b, and R3care each independently a 5- membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from triazole and tetrazole.

[0240] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the ,-145-Attorney Docket No.55773-739.601

[0241] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the-146-Attorney Docket No.55773-739.601 embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting of

[0242] In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6. In some embodiment, R4is substituted or unsubstituted C1- C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, or substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, or substituted or unsubstituted C1-C8 hydroxyalkyl.

[0243] In some embodiment, R4is substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiment, R4is substituted or unsubstituted C1- C8 alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R4is substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain wherein one or more of the carbon atoms is replaced with an O or N atom. In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O- (C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O- (C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), or -CH2-O-(C1-C4 haloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2- O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6heterocycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6 heterocycloalkyl).

[0244] In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, which is substituted with one or more halogen, -OR10, C1-C8 alkyl, or C3-C6 cycloalkyl.

[0245] In some embodiments, R4is substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is C3-C8 cycloalkyl. In some embodiments, R4is -147-Attorney Docket No.55773-739.601 monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl. In some embodiments, R4is.

[0246] In some embodiments, R4is substituted or unsubstituted C3-C8heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl. In some embodiments, R4is a 4- membered heterocycloalkyl. In some embodiments, R4is a 5-membered heterocycloalkyl. In some embodiments, R4is a 6-membered cycloalkyl. In some embodiments, R4is a 7- membered cycloalkyl. In some embodiments, R4is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R4is tetrahydrofuran or tetrahydropyran.

[0247] In some embodiments, each R6is independently halogen, -CN,-NO2, –NR8R9, -OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In some embodiments, each R6is independently halogen, -NR8R9, - OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)R9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10,–C(O)OR10, –C(O)NR8R9, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10, or C3-C8 cycloalkyl. In some embodiments, each R6is independently -NR8R9or -OR10. In some embodiments, each R6is independently C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R6is independently halogen. In some embodiments, each R6is independently H, Cl, F, or Br. In some embodiments, each R6is independently F. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently F, -OH, -CH3, or -CF3. In some embodiments, -148-Attorney Docket No.55773-739.601 each R6is independently F. In some embodiments, each R6is independently -OH. In some embodiments, each R6is independently -CF3. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently cyclopropyl. In some embodiments, each R6is cyclobutyl.

[0248] In some embodiments, two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a C3-C6 heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 5 memberedheterocycloalkyl. In some embodiments, two R6 combine together with the atom(s) to whichthey are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.

[0249] In some embodiments, R4is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, - CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or-149-Attorney Docket No.55773-739.601

[0250] In some embodiments, each R5is independently C1-C6 alkyl. In some embodiments, each R5is independently -CH2CH3 or -CH3. In some embodiments, each R5is independently -CH2CH3. In some embodiments, each R5is independently -CH3. In some embodiments, each R5is independently H.

[0251] In some embodiments, R5ais CH3. In some embodiments, R5ais H.

[0252] In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl.

[0253] In some embodiments, each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C10 cycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and -150-Attorney Docket No.55773-739.601 C3-C10 heterocycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0254] In some embodiments, each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C3- C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and C1-C6 alkyl. In some embodiments, each R10is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0255] In some embodiments, each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-memberedheteroaryl, each of which is substituted with one or more Ra. In some embodiments, eachR11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R11is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0256] In some embodiments, each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6 alkyl. In some embodiments, each R12is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl. -151-Attorney Docket No.55773-739.601

[0257] In some embodiments, each Rais independently selected from halogen, -OH, -CH3, - CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -OH, -CH3, -CF3, or - C(O)OH.

[0258] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0259] In some embodiments, the PGDH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.-152-Attorney Docket No.55773-739.601-153-Attorney Docket No.55773-739.601-154-Attorney Docket No.55773-739.601-155-Attorney Docket No.55773-739.601-156-Attorney Docket No.55773-739.601-157-Attorney Docket No.55773-739.601-158-Attorney Docket No.55773-739.601-159-Attorney Docket No.55773-739.601-160-Attorney Docket No.55773-739.601-161-Attorney Docket No.55773-739.601-162-Attorney Docket No.55773-739.601-163-Attorney Docket No.55773-739.601-164-Attorney Docket No.55773-739.601-165-Attorney Docket No.55773-739.601-166-Attorney Docket No.55773-739.601-167-Attorney Docket No.55773-739.601-168-Attorney Docket No.55773-739.601-169-Attorney Docket No.55773-739.601-170-Attorney Docket No.55773-739.601-171-Attorney Docket No.55773-739.601-172-Attorney Docket No.55773-739.601-173-Attorney Docket No.55773-739.601-174-Attorney Docket No.55773-739.601-175-Attorney Docket No.55773-739.601-176-Attorney Docket No.55773-739.601-177-Attorney Docket No.55773-739.601-178-Attorney Docket No.55773-739.601-179-Attorney Docket No.55773-739.601-180-Attorney Docket No.55773-739.601 EXAMPLES

[0260] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1: Effects of 15-PGDH inhibitor administration in aged mouse muscle

[0261] The effect of administration of a 15-PGDH inhibitor in cohorts of aged mice was assessed. Briefly, mice were male C57Bl / 6J mice that were either adults (12-15 months of age) or aged (23 months of age). Every 48 hours prior to testing, adult mice were orally administered a vehicle treatment and separate cohorts of aged mice were either orally administered a vehicle treatment or were orally administered the 15-PGDH inhibitor (10 mg / kg). Extensor digitorum longus muscle (EDL) was then isolated from mouse cohorts and stimulated using stimulation electrodes for in vitro force measurement assessments. FIG.1A shows the effects of vehicle or 15-PGDH inhibitor administration in adult or aged mice on absolute force (maximal force in millinewtons) in EDL muscle, and indicates that absolute force in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. FIG.1B shows the effects of vehicle or 15-PGDH inhibitor administration in adult or aged mice on specific force (force in millinewtons normalized to muscle weight in grams) in EDL muscle, and indicates that specific force in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. FIG.1C shows the effects of vehicle or 15-PGDH inhibitor administration in adult or aged mice on contraction rate in EDL muscle, and indicates that contraction rate in EDL muscle increased in aged mice administered the 15-PGDH inhibitor compared to aged mice administered vehicle. FIG.1D shows the effects of vehicle or 15-PGDH inhibitor administration in adult or aged mice on EDL muscle weight, and indicates that EDL muscle weight did not vary as a consequence of either mouse age or 15-PGDH inhibitor treatment. FIG.1E shows a comparison between the effects of multiple therapeutic molecules in multiple mouse models and targeted muscles on parameters such as muscle size, absolute force, and specific force, and indicates that the 15-PGDH inhibitor differentiates from other therapeutic molecules by improving muscle quality. -181-Attorney Docket No.55773-739.601 Example 2: Contraction time as a muscle responsive pharmacodynamic biomarker for a 15-PGDH inhibitor

[0262] The effects of a 15-PGDH inhibitor on in vivo muscle quality is determined. Tensiomyography (TMG), a non-invasive assessment of in vivo muscle quality, is performed in a subject. Stimulating electrodes connected to an electrical stimulator are connected to a muscle of the subject, and an electrical stimulus is provided to the muscle to induce a muscle contraction. TMG is used to assess contraction time in muscles comprising biceps femoris muscle and EDL muscle. Multiple muscle contractile parameters are measured, including contraction time (Tc, the time between 10% and 90% of the contraction), maximal displacement (Dm, the maximal displacement of the muscle contraction), delay time (Td, the time between the electrical impulse and 10% of the contraction), relaxation time (Tr, the time between 90% and 50% of the relaxation), and sustain time (Ts, the time between 50% of the contraction and 50% of the relaxation). The effects of administration of a 15-PGDH inhibitor on contraction time in muscle is measured, and a decrease in contraction time in muscle administered a 15-PGDH inhibitor indicates an improvement in muscle quality. When a 15- PGDH inhibitor is administered, contraction time in muscle is reduced. Example 3: Grip Strength as an Endpoint for a 15-PGDH inhibitor’s Effect on Fast Twitch Muscle

[0263] The effect of administration of a 15-PGDH inhibitor on grip strength in a subject is determined using hand-grip dynamometry. Grip strength is assessed in forearm muscles comprising flexor digitorum superficialis, pronator teres, flexor carpi radialis, flexor carpi ulnaris, or palmaris longus. When a 15-PGDH inhibitor is administered, grip strength in the subject is increased. Example 4: Timed-Up-and-Go as an Endpoint for a 15-PGDH inhibitor’s Effect on Fast Twitch Muscle

[0264] The effect of administration of a 15-PGDH inhibitor on time to complete a Timed- Up-and-Go (TUG) assessment in a subject is measured. The time it takes a subject to complete a TUG assessment as well as the time to complete the components of the TUG assessment (sit-to-stand, walking-out, turning, walking-in, turning around, and stand-to-sit) are measured. When a 15-PGDH inhibitor is administered, the time it takes a subject to complete a TUG assessment is reduced. -182-Attorney Docket No.55773-739.601

[0265] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. -183-

Claims

Attorney Docket No.55773-739.601 CLAIMS What is Claimed is:

1. A method for assessing muscle improvement in a subject, the method comprising: a) measuring one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof; b) administering to the subject a 15-hydroxyprostaglandin dehydrogenase (15- PGDH) inhibitor; and c) measuring one or more muscle quality parameters in the subject after being administered the 15-PGDH inhibitor.

2. The method of claim 1, wherein the one or more muscle quality parameters in step a) and / or step c) comprise grip strength.

3. The method of claim 1, wherein the one or more muscle quality parameters in step a) and / or step c) comprise time to complete a Timed-Up-and-Go assessment.

4. The method of claim 1, wherein prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased muscle contraction time in response to a stimulus relative to a predetermined threshold.

5. The method of claim 4, wherein after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having decreased muscle contraction time in response to a stimulus relative to step a).

6. The method of claim 2, wherein prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having reduced grip strength relative to a predetermined threshold.

7. The method of claim 6, wherein after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased grip strength relative to step a).

8. The method of claim 3, wherein prior to administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having increased time to complete a Timed- Up-and-Go assessment relative to a predetermined threshold. -184-Attorney Docket No.55773-739.601 9. The method of claim 8, wherein after administering to the subject the 15-PGDH inhibitor in step b), the subject is identified as having decreased time to complete a Timed- Up-and-Go assessment relative to step a).

10. The method of any one of claims 1-9, wherein measuring one or more muscle quality parameters in the subject in step a) identifies the subject as a candidate for treatment with the 15-PGDH inhibitor.

11. The method of any one of claims 1-10, wherein the subject has a disease or condition associated with reduced muscle quality.

12. The method of claim 11, wherein the disease or condition associated with reduced muscle quality is associated with aging.

13. The method of claim 12, wherein the disease or condition associated with aging is sarcopenia.

14. The method of claim 11, wherein the disease or condition associated with reduced muscle quality is spinal muscular atrophy.

15. The method of claim 11, wherein the disease or condition associated with reduced muscle quality is due to muscle injury.

16. The method of any one of claims 1-15, wherein the administering is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof.

17. The method of any one of claims 1-16, wherein the administering is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration.

18. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier.

19. The method of any one of claims 1-18, wherein the subject is administered a gastric inhibitory polypeptide (GIP) receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, an incretin mimetic, or a GLP-1 analog.

20. The method of any one of claims 1-19, wherein the subject is a human.

21. The method of any one of claims 1, 4-5, or 9-20, wherein the muscle comprises fast- twitch muscle fibers. -185-Attorney Docket No.55773-739.601 22. The method of any one of claims 1, 4-5, or 9-21, wherein the muscle is extensor digitorum longus.

23. The method of any one of claims 1-22, wherein the one or more muscle quality parameters is independent of muscle weight.

24. The method of any one of claims 1-23, wherein the subject is at least 60 years old.

25. The method of any one of claims 1-24, wherein the 15-PGDH inhibitor is selected from the group consisting of: a small molecule, an antibody or fragment thereof, a peptide inhibitor, an aptamer, an oligonucleotide inhibitor, and any combination thereof.

26. A method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject exhibits improvement in muscle quality as measured in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof.

27. A method for treating a subject with a muscle disorder, the method comprising: administering to the subject a therapeutically effective amount of a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to treat the muscle disorder, wherein the subject is identified as meeting a clinical endpoint, wherein the clinical endpoint is measured by an improvement in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof, and wherein the improvement is an improvement of at least 5% as compared to a baseline measurement in one or more of the muscle quality parameters.

28. A method for improving muscle quality in a subject with a muscle disorder, the method comprising: -186-Attorney Docket No.55773-739.601 administering to the subject a therapeutically effective amount of a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, wherein the subject exhibits improvement in muscle quality as measured in one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof, and wherein the improvement is an improvement of at least 5% as compared to a baseline measurement in one or more of the muscle quality parameters. -187-

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